Longitudinal analysis of quality of life following treatment with Asunercept plus reirradiation versus reirradiation in progressive glioblastoma patients.

PURPOSE: Glioblastoma is an aggressive malignant cancer of the central nervous system, with disease progression associated with deterioration of neurocognitive function and quality of life (QoL). As such, maintenance of QoL is an important treatment goal. This analysis presents time to deterioration (TtD) of QoL in patients with recurrent glioblastoma receiving Asunercept plus reirradiation (rRT) or rRT alone. METHODS: Data from patients with a baseline and ≥ 1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomisation to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥ 10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥ 10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of "Worse" in the MRC-Neurological status. Patients without a deterioration were censored at the last QoL assessment. Kaplan-Meier estimates were used to describe TtD and treatment groups (Asunercept + rRT or rRT alone) were compared using the log-rank test. RESULTS: Treatment with Asunercept + rRT was associated with significant improvement of TtD compared with rRT alone for QLQ-CL15 PAL overall QoL and physical functioning, and MRC Neurological Status (p ≤ 0.05). In the Asunercept + rRT group, QoL was maintained beyond progresison of disease (PoD). CONCLUSION: Treatment with Asunercept plus rRT significantly prolongs TtD and maintains QoL versus rRT alone in recurrent glioblastoma patients.

The use of tranexamic acid in microsurgery-is it safe?

BACKGROUND: An appropriate and adequate blood flow and oxygen delivery is paramount to free flap viability and success. The perioperative use of tranexamic acid (TXA) is associated with less risk for blood loss and blood transfusion in trauma, gynaecology, ear nose and throat (ENT) and orthopaedic surgery. As an antifibrinolytic drug, TXA has generally been avoided in microsurgery. The aim of this study is to evaluate the safety and benefit of using TXA in microsurgery. METHODS: We performed a retrospective single centre cohort study at the Pyramid Clinic, Zurich, Switzerland, including 98 free tissue transfers for breast reconstruction from 2011 to 2013. According to the estimated blood loss, up to 3 g TXA were administered intravenously in 63 free flaps perioperatively. RESULTS: No thrombosis (0%) of micro-anastomosis and 5 haematomas (10.0%) occurred after administration of TXA. In the control group, 1 thrombosis (3.0%) of a flap-vein and 6 haematomas (18.2%) occurred. Blood loss was significant lower (P<0.001) after administration of TXA. CONCLUSIONS: In this study, administration of TXA did not increase thrombosis in free tissue transfer and showed a reduced haematoma rate and significant reduction of blood loss. TXA is supposed to be safe and a reasonable adjunct for patients with anaemia and a higher intraoperative or postoperative blood loss.

Capsular contracture in implant based breast reconstruction-the effect of porcine acellular dermal matrix.

BACKGROUND: Irradiation of implant-based breast reconstructions (BR) is known to increase capsular contracture (CC) rates on average by 4-fold over non-irradiated reconstructions. The use of acellular dermal matrix (ADM) has been associated with lower CC rates in non-irradiated reconstructions (0-3%). Experimental and clinical studies suggest that ADM may also reduce CC rates in irradiated breasts. The aim of this study was to evaluate CC rates in non-irradiated and irradiated one- and two-stage BRs performed with the assistance of porcine ADM (PADM). METHODS: A single centre, retrospective, cohort study was designed from December 2008 to October 2012. A total of 200 immediate implant-based BRs were performed using PADM for inferior pole reinforcement. We included non-irradiated BR with a minimum follow up of 6 month from primary surgery (one stage) or from explantation of expander and implantation of the definitive implant (two stage). Of the postoperatively irradiated BR we included patients with 1 year or more follow up time from termination of radiotherapy. CC was graded using the conventional Spear-Baker classification and modified version for irradiated BR. According to the literature Grade III and IV CC were defined as clinically significant CC. RESULTS: Of 200 BRs with PADM, 122 were included in this study (84 non-irradiated and 38 irradiated). Sixty-five BR were one stage and 57 were two stage BR. Grade III/IV CC was remarkable low in non-irradiated (6%) and irradiated BR (13%). There was a non-significant trend to increased Grade III and IV CC in irradiated BR vs. non-irradiated BR (13% vs. 6%, P=0.216). In this study follow up time (P<0.001) and the stage of ADM reconstruction (two vs. one stage, P=0.022) were significant risk factors for occurrence of grade III/IV CC on univariate analysis and remained significant for the follow up time (P=0.013) and remarkable for the stages (P=0.093) in multivariate analysis. CONCLUSIONS: Our data support the current clinical evidence that ADM use in implant-based BR is associated with a reduced risk of CC when compared to the standard submuscular techniques in literature. The reduced risk is maintained in the setting of radiotherapy. Two stage procedures in our study population showed increased grade III/IV CC compared to one stage procedures with or without exposure to radiation.

An evaluation of resource utilisation of single stage porcine acellular dermal matrix assisted breast reconstruction: A comparative study.

OBJECTIVES: To evaluate resource utilization of single stage porcine acellular dermal matrix (ADM) assisted breast reconstruction compared with tissue expander (TE), latissimus dorsi flap and implant (LD/I) and latissimus dorsi flap and TE (LD/TE) reconstructive techniques. MATERIALS AND METHODS: Clinical data was collected for length of stay, operative time, additional hospitalisations and operative procedures, and outpatient appointments for 101 patients undergoing unilateral implant based breast reconstruction. Resources utilised by ADM (Strattice Reconstructive Tissue Matrix™) patients were analysed and compared to the resource usage of traditional techniques. RESULTS: 25 patients undergoing single stage ADM (ADM/I) were compared with 27 having TE, 32 having LD/I and 17 having LD/TE reconstructions. Follow up was 24 months. Compared to TE, ADM/I had similar length of stay and operative time, lower rate and number of additional procedures, fewer, shorter re-admissions (p < 0.05) and fewer appointments (p < 0.05). Compared to LD/TE, ADM/I had shorter length of stay and operative time (p < 0.05), lower rate and number of additional procedures, fewer, shorter re-admissions (p < 0.05) and fewer appointments (p < 0.05). Compared to LD/I, ADM/I had shorter length of stay (p < 0.05) and operative time (p < 0.05), fewer appointments, similar rate and number of additional procedures but required more and longer re-admissions. CONCLUSION: In our experience, unilateral single stage ADM/I was associated with fewer resources utilised in comparison with two staged TE and LD/TE reconstructions in both complication-free and complicated settings over a 24-month period, despite requiring aesthetic revision in 60.9% of patients. Compared to LD/I, resource utilisation was commensurate in complication-free and complicated settings.

A phase II, randomized, study of weekly APG101+reirradiation versus reirradiation in progressive glioblastoma.

PURPOSE: Preclinical data indicate anti-invasive activity of APG101, a CD95 ligand (CD95L)-binding fusion protein, in glioblastoma. EXPERIMENTAL DESIGN: Patients (N = 91) with glioblastoma at first or second progression were randomized 1:2 between second radiotherapy (rRT; 36 Gy; five times 2 Gy per week) or rRT+APG101 (400 mg weekly i.v.). Patient characteristics [N = 84 (26 patients rRT, 58 patients rRT+APG101)] were balanced. RESULTS: Progression-free survival at 6 months (PFS-6) rates were 3.8% [95% confidence interval (CI), 0.1-19.6] for rRT and 20.7% (95% CI, 11.2-33.4) for rRT+APG101 (P = 0.048). Median PFS was 2.5 (95% CI, 2.3-3.8) months and 4.5 (95% CI, 3.7-5.4) months with a hazard ratio (HR) of 0.49 (95% CI, 0.27-0.88; P = 0.0162) adjusted for tumor size. Cox regression analysis adjusted for tumor size revealed a HR of 0.60 (95% CI, 0.36-1.01; P = 0.0559) for rRT+APG101 for death of any cause. Lower methylation levels at CpG2 in the CD95L promoter in the tumor conferred a stronger risk reduction (HR, 0.19; 95% CI, 0.06-0.58) for treatment with APG101, suggesting a potential biomarker. CONCLUSIONS: CD95 pathway inhibition in combination with rRT is an innovative concept with clinical efficacy. It warrants further clinical development. CD95L promoter methylation in the tumor may be developed as a biomarker.

A prospective observational cohort safety study of 5106 platelet transfusions with components prepared with photochemical pathogen inactivation treatment.

BACKGROUND: Inactivation of pathogens and white blood cells in platelet (PLT) components with amotosalen and UVA light (INTERCEPT, Cerus Europe BV) has entered clinical practice in European blood centers. A prospective cohort study was implemented to characterize the safety profile of this new PLT component in a broad patient population. STUDY DESIGN AND METHODS: Apheresis or buffy-coat PLT components were leukoreduced, suspended in approximately 35 percent plasma and 65 percent PLT additive solution, and treated with the INTERCEPT process. Blood centers were requested to complete a safety data form after each transfusion. RESULTS: Data for 5106 INTERCEPT components administered to 651 patients were monitored. A total of 5051 (98.9%) transfusions and 609 (93.5%) patients had no reported reactions. Fifty-five (1.1%) transfusions were associated with adverse events, and 42 (0.8%) were possibly, probably, or related to the PLT transfusion. Adverse events occurred in 42 (6.4%) patients, but in only 32 (4.9%) patients was a causal relationship to PLT transfusion established. One reaction was serious, and no deaths were related to PLT transfusion. Among the transfusions reactions, the most frequent clinical events in descending frequency were chills, fever, dermatologic reactions, dyspnea, nausea or vomiting, and hypotension. No episodes of transfusion-related acute lung injury were reported. CONCLUSIONS: In this cohort study, 99.2 percent of transfusions were without reactions attributed to PLTs. INTERCEPT PLTs exhibited a safety profile similar to that previously reported for conventional PLT components.

Transfusion of 7-day-old amotosalen photochemically treated buffy-coat platelets to patients with thrombocytopenia: a pilot study.

BACKGROUND: Photochemical treatment (PCT) of platelets (PLTs) with amotosalen and ultraviolet A light to inactivate bacteria may facilitate extension of storage from 5 to 7 days. STUDY DESIGN AND METHODS: A randomized, double-blinded, crossover, noninferiority, single-site pilot study utilizing pooled buffy-coat PLTs was conducted. The primary endpoint was the 1-hour corrected count increment (CCI) after one transfusion each of 7-day-old PCT and reference (R) PLT components. Secondary endpoints included 1-hour count increment, time to next transfusion, hemostasis, transfusion reactions, and serious adverse events. RESULTS: Twenty patients with thrombocytopenia were randomly assigned: 9 to the PCT-R sequence and 11 to the R-PCT sequence. A significant treatment-by-period interaction was observed. Therefore, the first period only was also analyzed for the primary endpoint. Including both treatment periods, mean 1-hour CCI was 6587 +/- 4531 for PCT versus 8935 +/- 5478 for R-PLTs. For the first period only, mean 1-hour CCI was 8739 +/- 3785 for PCT versus 7433 +/- 5408 for R-PLTs. The upper bound of the one-sided 95 percent confidence interval of 2400 for the mean difference was higher than the specified noninferiority margin of 2200 for both analyses. Overall median time to next transfusion was 22 hours for PCT versus 27 hours for R-PLTs. Hemostasis was adequate and no transfusion reactions or serious adverse events were reported. CONCLUSIONS: Although this pilot study of a limited number of patients failed to show noninferiority within the specified noninferiority margin, 7-day-old PCT PLTs showed acceptable efficacy and safety for support of thrombocytopenia. The results, however, warrant evaluation in a larger trial of 7-day-old PCT PLTs.

Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India.

Miltefosine has previously been shown to cure 97% of cases of visceral leishmaniasis (VL) in Indian adults. Because approximately one-half of cases of VL occur in children, we evaluated use of the adult dosage of miltefosin (2.5 mg/kg per day for 28 days) in 80 Indian children (age, 2-11 years) with parasitologically confirmed infection in an open-label clinical trial. Clinical and parasitological parameters were reassessed at the end of treatment and 6 months later. One patient died of intercurrent pneumonia on day 6. The other 79 patients demonstrated no parasites after treatment, had marked clinical improvement, and were deemed initially cured. Three patients had relapse, and 1 patient was lost to follow-up. The final cure rate was 94% for all enrolled patients and 95% for evaluable patients. Side effects included mild-to-moderate vomiting or diarrhea (each in approximately 25% of patients) and mild-to-moderate, transient elevations in the aspartate aminotransferase level during the early treatment phase (in 55%). This trial indicates that miltefosine is as effective and well tolerated in Indian children with VL as in adults and that it can be recommended as the first choice for treatment of childhood VL in India.

Crossover randomized comparison of intravenous versus intravenous/oral mesna in soft tissue sarcoma treated with high-dose ifosfamide.

PURPOSE: We conducted our study to determine the pharmacokinetics (PK) and clinical efficacy of oral mesna in patients receiving ifosfamide for soft tissue sarcoma. EXPERIMENTAL DESIGN: Seventeen patients were enrolled in a randomized prospective Phase I/II study. Seventeen patients were exposed to study medication. Ifosfamide was given at a dose of 2 g/m2/day for 5 days on a 21-day cycle. Before the first cycle, all patients were randomized onto a crossover design and received either the approved i.v. or i.v./oral mesna regimen, with crossover for the second cycle of chemotherapy. The i.v. mesna regimen consisted of dosings (20% ifosfamide dose) at 0, 4, and 8 h. The i.v./oral arm consisted of an i.v. mesna dosing (20% ifosfamide dose) at 0 h, followed by oral tablet dosing (40% ifosfamide dose) at 2 and 6 h. In-patient clinical monitoring and phlebotomy and urine sampling for mesna, dimesna, and ifosfamide PK were performed on all chemotherapy days. RESULTS: Thirteen patients were evaluable for PK and 17 for efficacy and toxicity. No significant differences were detected in the plasma PK of the concomitantly infused ifosfamide. Rates of hemorrhagic cystitis were similar across mesna schedules. Four of 10 evaluable patients demonstrated objective response. CONCLUSION: On the basis of our study, an i.v./oral mesna regimen is at least as uroprotective as the approved i.v. regimen. The i.v./oral regimen will improve patient tolerance and convenience, allow for a reduction in elective hospitalizations for ifosfamide chemotherapy, reduce the potential morbidity associated with inpatient administration of chemotherapy, and likely result in decreased costs of care.

Inhibin B on the day of HCG-administration is a predictive factor for failure in assisted reproduction cycles.

MATERIALS AND METHODS: This retrospective study was carried out in order to assess the value of inhibin B as a predictive factor for the assisted reproduction-outcome. Inhibin B on the day of HCG-administration (ovulation induction) was measured in 15 pregnant and 16 non-pregnant patients (defined as positive serum-HCG) and compared by single and multiple logistic regression analysis with classical predictive factors such as estrogen and oocyte number. Both groups were similar with respect to age and cause of infertility. RESULTS: While estrogen, FSH and LH at the HCG-day did not differ, inhibin B, the number of cumulus oocyte complexes and metaphase II -oocytes were statistically significantly different. In a single variable logistic model inhibin B, cumulus oocyte complexes and metaphase II oocytes showed significant correlation with pregnancy. When reassessed in a multiple variable logistic model only inhibin B maintained a considerable influence. Further inspection revealed, that the predictive inhibin B value at HCG-day <1200 pg/ml for failure of ART (assisted reproduction techniques) was 91%. Inhibin >1200 pg/ml showed 70% predictivity for pregnancy. CONCLUSION: In comparison to classical parameters inhibin B at HCG-day seems to be the better prognostic factor for the outcome of ART. Inhibin B <1200 pg/ml seems to be highly predictive for failure of ART.

Drug interaction of spirapril hydrochloride monohydrate and hydrochlorothiazide. A clinical study to compare the pharmacokinetics after administration of spirapril hydrochloride monohydrate tablets, hydrochlorothiazide tablets and fixed combination bi-layer tablets.

The potential influence of concomitantly administered hydrochlorothiazide (CAS 58-93-5) on the pharmacokinetics of spirapril (CAS 94841-17-5)/spiraprilat (CAS 83602-05-5) and of concomitantly administered spirapril on the pharmacokinetics of hydrochlorothiazide was investigated in an open, randomised, 3-way crossover study in 12 healthy male subjects. The test drug was a newly developed bi-layer tablet containing a fixed combination of spirapril hydrochloride monohydrate and hydrochlorothiazide (Quadroplus). The reference formulations were tablets containing solely spirapril hydrochloride monohydrate (Quadropril) or hydrochlorothiazide (produced exclusively for study medication). For spirapril, spiraprilat and hydrochlorothiazide the 90% confidence intervals of the AUC(0-infinity) as a measure for the extent of absorption were entirely included within the equivalence range of 0.8 to 1.25 and the 90% confidence intervals of the Cmax as a measure for the rate of absorption were entirely included within the extended equivalence range of 0.7 to 1.43. Therefore, bioequivalence was concluded for the test and reference formulations. The results suggest that hydrochlorothiazide does not interact in the fixed combination with the pharmacokinetics of spirapril and vice versa.

Oral miltefosine treatment in children with mild to moderate Indian visceral leishmaniasis.

BACKGROUND: Miltefosine is the first oral drug with demonstrable success in treating visceral leishmaniasis in adults. Because approximately one-half of the visceral leishmaniasis patients worldwide are children, we performed a Phase I/II dose ranging study in the pediatric population in India. METHODS: Thirty-nine (39) children (defined as < 12 years of age) with visceral leishmaniasis demonstrated by parasites in splenic aspirates, were treated with oral miltefosine daily for 28 days: 21 patients received 1.5 mg/kg/day (Group A); and 18 patients received 2.5 mg/kg/day (Group B). About one-half of these children had failed prior antileishmanial treatment. RESULTS: All patients were parasitologically negative and symptomatically improved by the end of therapy on Day 28 of therapy; the initial parasitologic cure rate was 100%. Two patients in each treatment group relapsed with fever, splenomegaly and parasite-positive splenic aspirates by the end of the 6-month follow-up. The per protocol final clinical cure rate was 19 of 21 = 90% in Group A and 15 of 17 = 88% in Group B. Miltefosine was well-tolerated. As per the adult experience, gastrointestinal adverse events were seen: 33 and 39% of children experienced vomiting and 5 and 17% experienced diarrhea in Groups A and B, respectively, but all episodes were mild to moderate in severity and commonly lasted <1 day without symptomatic treatment. CONCLUSION: Oral miltefosine was safe and approximately 90% effective in this initial clinical trial of childhood visceral leishmaniasis.

Oral miltefosine for Indian visceral leishmaniasis.

BACKGROUND: There are 500,000 cases per year of visceral leishmaniasis, which occurs primarily in the Indian subcontinent. Almost all untreated patients die, and all the effective agents have been parenteral. Miltefosine is an oral agent that has been shown in small numbers of patients to have a favorable therapeutic index for Indian visceral leishmaniasis. We performed a clinical trial in India comparing miltefosine with the most effective standard treatment, amphotericin B. METHODS: The study was a randomized, open-label comparison, in which 299 patients 12 years of age or older received orally administered miltefosine (50 or 100 mg [approximately 2.5 mg per kilogram of body weight] daily for 28 days) and 99 patients received intravenously administered amphotericin B (1 mg per kilogram every other day for a total of 15 injections). RESULTS: The groups were well matched in terms of age, weight, proportion with previous failure of treatment for leishmaniasis, parasitologic grade of splenic aspirate, and splenomegaly. At the end of treatment, splenic aspirates were obtained from 293 patients in the miltefosine group and 98 patients in the amphotericin B group. No parasites were identified, for an initial cure rate of 100 percent. By six months after the completion of treatment, 282 of the 299 patients in the miltefosine group (94 percent [95 percent confidence interval, 91 to 97]) and 96 of the 99 patients in the amphotericin B group (97 percent) had not had a relapse; these patients were classified as cured. Vomiting and diarrhea, generally lasting one to two days, occurred in 38 percent and 20 percent of the patients in the miltefosine group, respectively. CONCLUSIONS: Oral miltefosine is an effective and safe treatment for Indian visceral leishmaniasis. Miltefosine may be particularly advantageous because it can be administered orally. It may also be helpful in regions where parasites are resistant to current agents.

Novel formulations of cetrorelix acetate in healthy men: pharmacodynamic effects and noncompartmental pharmacokinetics.

The objective of this study was to investigate the effects on the pharmacodynamics and noncompartmental pharmacokinetics after weekly subcutaneous administration of novel formulations of cetrorelix acetate in healthy men. In a randomized parallel-group study, single subcutaneous doses of cetrorelix acetate (concentration: 2.5 mg peptide base/ml) dissolved in aqueous gluconic acid (CET/glu, dose: 5 or 10 mg peptide base) or in water (CET/wat, dose: 10 mg peptide base) were given to 36 subjects once weekly in the morning for 4 weeks. Cetrorelix plasma, serum testosterone, luteinizing hormone, andfollicle-stimulating hormone concentrations were monitored after each administration for 1 week, with extensive profiling after the first and fourth administration. Cetrorelix plasma concentrations were analyzed by radioimmunoassay and serum hormone concentrations by enzyme immunoassays. At least half-maximum testosterone suppression started with all treatments within less than 1 day. Deepest and longest testosterone suppression was achieved by 10 mg CET/glu. Duration of atleasthalf-maximum suppression was after the first dose median of 82 hours and after the fourth dose median of 122 hours, respectively. Substantial suppression was also evidentfor luteinizing hormone (LH) and, to a lesser extent, forfollicle-stimulating hormone (FSH). On average, Cmax was nearly doubled after single and multiple doses, and AUC(tau) was increased by about 50% after single doses and about 30% after multiple doses of 10 mg CET/glu as compared to 10 mg CET/wat. For tmax and t1/2, no significant differences were found between formulations. It was concluded that testosterone suppression increased with weekly subcutaneous administrations of 10 mg CET/glu. Compared to CET/wat, bioavailability and duration of suppression were increased with CET/glu.